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Neurogenetics: An update

cases compared to controls. When the four SNPs
of CYP2C9 and CYP2C19 were analysed using
a haplotype approach, a signifi cant difference
in the distribution of the C-C-G-G haplotype
was observed between the cases and controls.
These results showed that CYP2C9 genetic polymorphisms
(particularly the *3 allele) were
associated with a high risk of epileptic patients
developing phenytoin-induced neurological
toxicity.9

The other important implication of pharmacogenetics
in epilepsy care has been the capacity to
predict carbamazepine-related adverse effects
on the skin. The genetic marker HLA-B*1502,
fi rst identifi ed in the Chinese population
living in Taiwan, has been strongly associated
with carbamazepine-induced hypersensitivity
reactions, including fatal Stevens–Johnson
reaction, with an OR of 72, an association that
occurs primarily in Asians because of the high
frequency of this allele.10 The FDA has suggested
that patients with the HLA-B1502 allele should
not be started on carbamazepine unless absolutely
necessary, and starting any antiepileptic drug in
these subjects also needs to be considered very
carefully, since other antiepileptic drugs also
have an increased risk in those with this gene
mutation.

Neurogenetics: An update 19
Update on specific neurological
conditions
Cerebrovascular disorders
A concerted effort was made by a number
of consortia such as the International Stroke
Genetics Consortium, the Wellcome Trust Case–
Control Consortium and other similar groups to
determine the clinically important gene mutations
and polymorphisms for cerebrovascular diseases.
This effort turned out to be more diffi cult that
anticipated.11

Among the most recent validated discoveries
are one associated with atrial fi brillation and
another previously linked with coronary artery
disease (CAD) and myocardial infarction
(MI). The former includes 2 sequence variants
on Chr 4q25 seen in 35% of the Caucasian
population.12 The variants were found adjacent
to PITX2, a gene related to the heart’s structural
symmetry. The second one is a locus on 9p21.3,
and this association has been established to be
independent of the infl uence of CAD and other
stroke risk factors for stroke.13 WMHIs, which
has a heritability of 55%–70%, is a marker of
cerebral small-vessel disease and is a hallmark of
cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy
(CADASIL, due to Notch 3 mutations); mitochondrial
encephalomyopathy, lactic acidosis,
and stroke-like episodes (MELAS); Fabry disease;
cerebral amyloid angiopathy and COL4A1-
related cerebrovascular disease.14 A recent study
of the occurrence of transient ischaemic attacks
(TIAs) and strokes reported an association of a
defi ned mitochondrial DNA haplogroup with the
risk of disease, but not in 340 controls with acute
coronary syndrome from the same population,
as well as 2393 independent population controls.
The mitochondrial subhaplogroup K appeared
to have a protective effect (OR 0.54, 95% CI
0.39–0.75).15

Parkinsonism
Carriers of the gaucher gene have a fi ve-fold
increased risk for Parkinson disease (PD).16
Though fi rst noted specifi cally in Azhkenazi Jews,
who have a gene frequency of 12% for Gaucher
disease, such a carrier status for Gaucher disease
was found to increase the risk for PD in other
ethnic groups also. This carrier status in the non-
Azhkenazi population is a good example of a rare
variant. Another interesting recently discovered
association is that of an SNP in the vitamin D
receptor and an earlier age of onset of PD.17 This
same SNP has shown an association with multiple
sclerosis (MS) and Alzheimer disease (AD)
as well. A third major gene is the parkin gene,
with Hispanic or North European descendants
having thrice the risk.18 Heterogeneous deletion
of the TH (tyrosine hydroxylase) gene is also
found to increase the risk for PD.19 Association
of PD with an HLA gene has also been reported.20
Genetic types of parkinsonism such as Park
3,5,8,11 and 13 are autosomal dominant types
and indistinguishable from sporadic idiopathic
types. Park types 2,6,7,9,10,14 are autosomal
recessive and are characterized by young onset,
whereas Park12 has an x-linked recessive mode
of inheritance.

Multiple sclerosis
Before the GWAS era, the only confi rmed genetic
marker of MS was a major histocompatibility
complex (MHC) on chromosome 6p21.21 The fi rst
GWAS in MS demonstrated that SNPs within the
interleukin-2 receptor, alpha gene IL2RA and the
interleukin-7 receptor, alpha gene IL7RA were the
most probable markers of genetic susceptibility
to MS.22 Further, the HLA-DRA locus has also
been confi rmed as a heritable risk factor for MS.
These genes are linked to the regulatory pathways
of immune response, which are known to play an
important role in the pathophysiology of MS. A
meta-analysis following the GWAS investigations
on MS led to the acceptance of other signifi cant
20 SUNIL K. NARAYAN, C. ADITHAN, P.F. CHINNERY
genes such as TNFRSF (tumour necrosis factor
receptor superfamily) member 1A gene, IRF8
(interferon regulatory factor 8) gene and CD6
molecule gene. These have all been shown to have
an effect size of OR 1.2–1.6.23 GPC5, a heparin
sulphate proteoglycan gene, was also found to
have a disease risk replicated independently.24
Essential tremor

This autosomal dominant familial condition
shows variable penetrance. An association with
PD has also been postulated. The GWAS demonstrated
strong association with the LINGO1
variant in an Icelandic population.25 The gene has
been implicated in CNS axon degeneration and
oligodendrocyte maturation. A meta-analysis
has also shown a weak association between the
LINGO1 gene and PD.25a
Multisystem atrophy (MSA)

The GWAS in MSA showed an association with
the SNCA locus with an OR of 6.2, though a
more realistic association was seen in another
European study with an OR of 1.75.26 SNCA
is a fi brillary form of alpha synuclein seen as a
primary pathology in the glial cytoplasm in MSA.
Autistic spectral disorders (ASDs)
The named specifi c neurogenetic syndromes
of autism account only for 1%–2% of cases.
Recently, common genetic variants such as copy
number variations (CNVs) have been detected
to be associated with autism using powerful
microarray techniques. Microarray should be
the investigation of choice for the work-up of
ASDs, unexplained developmental delays, mental
retardation and multiple congenital anomalies.27
Chromosomal high-density SNP microarrays can
identify chromosomal anomalies 5–7 times more
frequently than conventional methods. From
a 750 multiplex family genetic source, a GWAS
revealed deletion of 16p11.2. Duplication of the
same locus was also noted in another family
multiplex. These micro deletions/duplications
account for about 1% all ASD cases.28 The 5p14.1
locus between the CDH9 and 10 foci has also
been found to be replicated.29 CNV studies have
also confi rmed previously recorded associations
such as NIGN1, ASTN2, which encode neuronal
cell adhesion molecules. The ubiquitin pathway
genes such as UBE3A, PARK2, RFWD2 and
FBX040 were also found to have signifi cant CNVs
in ASD patients compared with controls.30
Duchenne and Becker muscular dystrophy
Duchenne muscular dystrophy (DMD) accounts
for most patients with an inherited muscle disease
in a neuromuscular clinic. The dystrophin gene
codes for a protein called dystrophin, which
is a large rod-like protein that connects the
actin cytoskeleton to the dystrophin complex
at the sarcolemma.31 Deletions or duplications
that produce a reading frame shift are the most
common type of mutation, which leads to total
or severe depletion of the dystrophin protein.
This loss of dystrophin causes muscle damage
during repeated muscle contractions because of
disruption of the connection. A clinical diagnosis
can be made confi dently in most situations
but the genetic diagnosis relies on detection of
deletion or duplication of the dystrophin gene.
If screening for large deletions and duplications
is negative, dystrophin gene sequencing should
be performed to look for point mutations or
deletions or small insertions responsible for the
reading frame shift.32 An exact genetic diagnosis is
useful for predicting the prognosis since the type
of mutation predicts the phenotype in 90% cases.
Drugs are also in several phases of development.
These are capable of skipping specifi c parts of the
dystrophin gene to repair the reading frame, for
which it is imperative that the exact details of the
mutation are known.

In Becker muscular dystrophy (BMD),
point mutations or in-frame deletions lead to
truncated but partially functional dystrophin
Neurogenetics: An update 21
protein. Because of the late presentation, this
forms part of the differential diagnosis of limb–
girdle muscular dystrophy (LGMD). Muscle
biopsy can be diagnostic; BMD is suggested by
decreased dystrophin levels/altered migration
on immunoblotting, and DMD carrier status
by a mosaic pattern of dystrophin-positive and
-negative fi bres.

Myotonic dystrophy
This is the second most common inherited
muscle disease with distal myopathy, myotonia
and characteristic facies. This multisystem disease
is caused by repeat expansion mutations in either
the DMPK (type1) or CNBP (type 2) genes, both
inherited in an autosomal dominant fashion, with
DM1 often showing marked anticipation due to
expansion of the CTG trinucleotide repeats in
the 3’untranslated region of the DMPK region.33
The size of the repeat correlates with disease
severity, with classic DM1 having 50–100 repeats
and congenital DM1 having >